Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

Jean E. Vance1
1University of Alberta, Edmonton, AB, Canada

Tóm tắt

SummaryDysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS). However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE), a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.

Từ khóa


Tài liệu tham khảo

Aqul, 2011, Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment, J. Neurosci., 31, 9404, 10.1523/JNEUROSCI.1317-11.2011

Bales, 2009, Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice, J. Neurosci., 29, 6771, 10.1523/JNEUROSCI.0887-09.2009

Bar-On, 2008, Statins reduce neuronal alpha-synuclein aggregation in in vitro models of Parkinson’s disease, J. Neurochem., 105, 1656, 10.1111/j.1471-4159.2008.05254.x

Barrett, 2012, The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol, Science, 336, 1168, 10.1126/science.1219988

Baudry, 2003, Postnatal development of inflammation in a murine model of Niemann-Pick type C disease: immunohistochemical observations of microglia and astroglia, Exp. Neurol., 184, 887, 10.1016/S0014-4886(03)00345-5

Beffert, 2004, Functions of lipoprotein receptors in neurons, J. Lipid Res., 45, 403, 10.1194/jlr.R300017-JLR200

Bien-Ly, 2012, Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice, J. Neurosci., 32, 4803, 10.1523/JNEUROSCI.0033-12.2012

Björkhem, 2010, Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge, Biochem. Biophys. Res. Commun., 396, 46, 10.1016/j.bbrc.2010.02.140

Björkhem, 2006, Oxysterols and Alzheimer’s disease, Acta Neurol. Scand. Suppl., 114, 43, 10.1111/j.1600-0404.2006.00684.x

Björkhem, 2011, High levels of 15-oxygenated steroids in circulation of patients with multiple sclerosis: fact or fiction?, J. Lipid Res., 52, 170, 10.1194/jlr.D011072

Björnsson, 1994, Regulation of VLDL secretion in primary culture of rat hepatocytes: involvement of cAMP and cAMP-dependent protein kinases, Eur. J. Clin. Invest., 24, 137, 10.1111/j.1365-2362.1994.tb00979.x

Bodovitz, 1996, Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein, J. Biol. Chem., 271, 4436, 10.1074/jbc.271.8.4436

Bosco, 2006, Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization, Nat. Chem. Biol., 2, 249, 10.1038/nchembio782

Boyles, 1985, Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system, J. Clin. Invest., 76, 1501, 10.1172/JCI112130

Boyles, 1989, A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve, J. Clin. Invest., 83, 1015, 10.1172/JCI113943

Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science, 232, 34, 10.1126/science.3513311

Bryleva, 2010, ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD, Proc. Natl. Acad. Sci. USA, 107, 3081, 10.1073/pnas.0913828107

Bu, 2009, Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy, Nat. Rev. Neurosci., 10, 333, 10.1038/nrn2620

Burns, 2003, Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo, J. Neurosci., 23, 5645, 10.1523/JNEUROSCI.23-13-05645.2003

Castellano, 2011, Human apoE isoforms differentially regulate brain amyloid-β peptide clearance, Sci. Transl. Med., 3, 89, 10.1126/scitranslmed.3002156

Corder, 1993, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families, Science, 261, 921, 10.1126/science.8346443

Corder, 1994, Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease, Nat. Genet., 7, 180, 10.1038/ng0694-180

Cramer, 2012, ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models, Science, 335, 1503, 10.1126/science.1217697

Crews, 2008, Alpha-synuclein alters Notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice, J. Neurosci., 28, 4250, 10.1523/JNEUROSCI.0066-08.2008

de Lau, 2006, Serum cholesterol levels and the risk of Parkinson’s disease, Am. J. Epidemiol., 164, 998, 10.1093/aje/kwj283

Dietschy, 2001, Cholesterol metabolism in the brain, Curr. Opin. Lipidol., 12, 105, 10.1097/00041433-200104000-00003

Dietschy, 2004, Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal, J. Lipid Res., 45, 1375, 10.1194/jlr.R400004-JLR200

Distl, 2003, Cholesterol storage and tau pathology in Niemann-Pick type C disease in the brain, J. Pathol., 200, 104, 10.1002/path.1320

Ehehalt, 2003, Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts, J. Cell Biol., 160, 113, 10.1083/jcb.200207113

Elder, 2007, Elevated plasma cholesterol does not affect brain Abeta in mice lacking the low-density lipoprotein receptor, J. Neurochem., 102, 1220, 10.1111/j.1471-4159.2007.04614.x

Fagan, 1998, Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (−/−) mice but impaired clearance of axonal degeneration products following injury, Exp. Neurol., 151, 314, 10.1006/exnr.1998.6818

Fantini, 2011, The fusogenic tilted peptide (67–78) of α-synuclein is a cholesterol binding domain, Biochim. Biophys. Acta, 1808, 2343, 10.1016/j.bbamem.2011.06.017

Fassbender, 2002, Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide, Neurology, 59, 1257, 10.1212/WNL.59.8.1257

Fryer, 2005, The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice, J. Biol. Chem., 280, 25754, 10.1074/jbc.M502143200

Grimm, 2012, The role of APP proteolytic processing in lipid metabolism, Exp. Brain Res., 217, 365, 10.1007/s00221-011-2975-6

Gupta, 2011, Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging, Neurology, 76, 1091, 10.1212/WNL.0b013e318211c352

Hawes, 2010, Pre-synaptic defects of NPC1-deficient hippocampal neurons are not directly related to plasma membrane cholesterol, J. Neurochem., 114, 311, 10.1111/j.1471-4159.2010.06768.x

Hayashi, 2004, Glial lipoproteins stimulate axon growth of central nervous system neurons in compartmented cultures, J. Biol. Chem., 279, 14009, 10.1074/jbc.M313828200

Hayashi, 2009, Protection of neurons from apoptosis by apolipoprotein E-containing lipoproteins does not require lipoprotein uptake and involves activation of phospholipase Cgamma1 and inhibition of calcineurin, J. Biol. Chem., 284, 29605, 10.1074/jbc.M109.039560

Hayashi, 2007, Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1, J. Neurosci., 27, 1933, 10.1523/JNEUROSCI.5471-06.2007

Herz, 2001, Lipoprotein receptors: beacons to neurons?, Trends Neurosci., 24, 193, 10.1016/S0166-2236(00)01768-9

Herz, 2001, The LDL receptor gene family: (un)expected signal transducers in the brain, Neuron, 29, 571, 10.1016/S0896-6273(01)00234-3

Hirsch-Reinshagen, 2007, Cholesterol metabolism, apolipoprotein E, adenosine triphosphate-binding cassette transporters, and Alzheimer’s disease, Curr. Opin. Lipidol., 18, 325, 10.1097/MOL.0b013e32813aeabf

Hirsch-Reinshagen, 2004, Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain, J. Biol. Chem., 279, 41197, 10.1074/jbc.M407962200

Hirsch-Reinshagen, 2005, The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease, J. Biol. Chem., 280, 43243, 10.1074/jbc.M508781200

Hu, 2008, Total cholesterol and the risk of Parkinson disease, Neurology, 70, 1972, 10.1212/01.wnl.0000312511.62699.a8

Huang, 2007, Lower low-density lipoprotein cholesterol levels are associated with Parkinson’s disease, Mov. Disord., 22, 377, 10.1002/mds.21290

Hudry, 2010, Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer’s disease, Mol. Ther., 18, 44, 10.1038/mt.2009.175

Ignatius, 1986, Expression of apolipoprotein E during nerve degeneration and regeneration, Proc. Natl. Acad. Sci. USA, 83, 1125, 10.1073/pnas.83.4.1125

Jiang, 2011, A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma, J. Lipid Res., 52, 1435, 10.1194/jlr.D015735

Jick, 2000, Statins and the risk of dementia, Lancet, 356, 1627, 10.1016/S0140-6736(00)03155-X

Karasinska, 2011, Cholesterol metabolism in Huntington disease, Nat. Rev. Neurol., 7, 561, 10.1038/nrneurol.2011.132

Karten, 2002, Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons, J. Neurochem., 83, 1154, 10.1046/j.1471-4159.2002.01220.x

Karten, 2003, Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons, J. Biol. Chem., 278, 4168, 10.1074/jbc.M205406200

Karten, 2005, Generation and function of astroglial lipoproteins from Niemann-Pick type C1-deficient mice, Biochem. J., 387, 779, 10.1042/BJ20041694

Karten, 2006, The Niemann-Pick C1 protein in recycling endosomes of presynaptic nerve terminals, J. Lipid Res., 47, 504, 10.1194/jlr.M500482-JLR200

Kim, 2009, Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance, Neuron, 64, 632, 10.1016/j.neuron.2009.11.013

Koistinaho, 2004, Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides, Nat. Med., 10, 719, 10.1038/nm1058

Kojro, 2001, Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha–secretase ADAM 10, Proc. Natl. Acad. Sci. USA, 98, 5815, 10.1073/pnas.081612998

Lee, 2012, Apolipoprotein E promotes β-amyloid trafficking and degradation by modulating microglial cholesterol levels, J. Biol. Chem., 287, 2032, 10.1074/jbc.M111.295451

Leoni, 2011, Oxysterols as biomarkers in neurodegenerative diseases, Chem. Phys. Lipids, 164, 515, 10.1016/j.chemphyslip.2011.04.002

Leoni, 2010, Links between ApoE, brain cholesterol metabolism, tau and amyloid beta-peptide in patients with cognitive impairment, Biochem. Soc. Trans., 38, 1021, 10.1042/BST0381021

Liscum, 1989, The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts, J. Cell Biol., 108, 1625, 10.1083/jcb.108.5.1625

Liu, 2009, Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse, Proc. Natl. Acad. Sci. USA, 106, 2377, 10.1073/pnas.0810895106

Longenberger, 2011, Simvastatin and other HMG-CoA reductase inhibitors on brain cholesterol levels in Alzheimer’s disease, Curr. Alzheimer Res., 8, 434, 10.2174/156720511795745393

Lopez, 2011, Anatomically defined neuron-based rescue of neurodegenerative Niemann-Pick type C disorder, J. Neurosci., 31, 4367, 10.1523/JNEUROSCI.5981-10.2011

Mailman, 2011, Inhibition of neuronal cholesterol biosynthesis with lovastatin leads to impaired synaptic vesicle release even in the presence of lipoproteins or geranylgeraniol, J. Neurochem., 119, 1002, 10.1111/j.1471-4159.2011.07474.x

Maity, 2005, Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly, PNAS, 102, 17026, 10.1073/pnas.0507848102

Mann, 2000, Cholesterol modification of proteins, Biochim. Biophys. Acta, 1529, 188, 10.1016/S1388-1981(00)00148-7

Marwarha, 2011, The oxysterol 27-hydroxycholesterol regulates α-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors – relevance to Parkinson’s disease, J. Neurochem., 119, 1119, 10.1111/j.1471-4159.2011.07497.x

Masliah, 1995, Neurodegeneration in the central nervous system of apoE-deficient mice, Exp. Neurol., 136, 107, 10.1006/exnr.1995.1088

Mauch, 2001, CNS synaptogenesis promoted by glia-derived cholesterol, Science, 294, 1354, 10.1126/science.294.5545.1354

Michikawa, 2000, Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture, J. Neurochem., 74, 1008, 10.1046/j.1471-4159.2000.0741008.x

Nathan, 1994, Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro, Science, 264, 850, 10.1126/science.8171342

Nieweg, 2009, Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats, J. Neurochem., 109, 125, 10.1111/j.1471-4159.2009.05917.x

Oitzl, 1997, Severe learning deficits in apolipoprotein E-knockout mice in a water maze task, Brain Res., 752, 189, 10.1016/S0006-8993(96)01448-5

Peake, 2012, Normalization of cholesterol homeostasis by 2-hydroxypropyl-β-cyclodextrin in neurons and glia from Niemann-Pick C1 (NPC1)-deficient mice, J. Biol. Chem., 287, 9290, 10.1074/jbc.M111.326405

Peake, 2011, Niemann-Pick Type C1 deficiency in microglia does not cause neuron death in vitro, Biochim. Biophys. Acta, 1812, 1121, 10.1016/j.bbadis.2011.06.003

Popko, 1993, Nerve regeneration occurs in the absence of apolipoprotein E in mice, J. Neurochem., 60, 1155, 10.1111/j.1471-4159.1993.tb03268.x

Porter, 2006, Cholesterol precursors and facial clefting, J. Clin. Invest., 116, 2322, 10.1172/JCI29872

Porter, 2011, Malformation syndromes caused by disorders of cholesterol synthesis, J. Lipid Res., 52, 6, 10.1194/jlr.R009548

Porter, 1996, Cholesterol modification of hedgehog signaling proteins in animal development, Science, 274, 255, 10.1126/science.274.5285.255

Posse de Chaves, 1997, Role of lipoproteins in the delivery of lipids to axons during axonal regeneration, J. Biol. Chem., 272, 30766, 10.1074/jbc.272.49.30766

Posse de Chaves, 2000, Uptake of lipoproteins for axonal growth of sympathetic neurons, J. Biol. Chem., 275, 19883, 10.1074/jbc.275.26.19883

Quan, 2003, Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse, Brain Res. Dev. Brain Res., 146, 87, 10.1016/j.devbrainres.2003.09.015

Radhakrishnan, 2008, Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance, Cell Metab., 8, 512, 10.1016/j.cmet.2008.10.008

Rantham Prabhakara, 2008, Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on tyrosine hydroxylase and alpha-synuclein in human neuroblastoma SH-SY5Y cells, J. Neurochem., 107, 1722, 10.1111/j.1471-4159.2008.05736.x

Reiner, 1988, Differential loss of striatal projection neurons in Huntington disease, Proc. Natl. Acad. Sci. USA, 85, 5733, 10.1073/pnas.85.15.5733

Rigamonti, 2000, Wild-type huntingtin protects from apoptosis upstream of caspase-3, J. Neurosci., 20, 3705, 10.1523/JNEUROSCI.20-10-03705.2000

Rosenbaum, 2010, Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells, Proc. Natl. Acad. Sci. USA, 107, 5477, 10.1073/pnas.0914309107

Roy, 2011, Prospects of statins in Parkinson disease, Neuroscientist, 17, 244, 10.1177/1073858410385006

Russell, 2009, Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain, Annu. Rev. Biochem., 78, 1017, 10.1146/annurev.biochem.78.072407.103859

Sanan, 1994, Apolipoprotein E associates with beta amyloid peptide of Alzheimer’s disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3, J. Clin. Invest., 94, 860, 10.1172/JCI117407

Sano, 2011, A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease, Neurology, 77, 556, 10.1212/WNL.0b013e318228bf11

Sarna, 2003, Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease, J. Comp. Neurol., 456, 279, 10.1002/cne.10522

Selkoe, 2001, Clearing the brain’s amyloid cobwebs, Neuron, 32, 177, 10.1016/S0896-6273(01)00475-5

Selkoe, 2002, Alzheimer’s disease is a synaptic failure, Science, 298, 789, 10.1126/science.1074069

Shafaati, 2011, Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer’s patients with the Swedish APP 670/671 mutation, J. Lipid Res., 52, 1004, 10.1194/jlr.M014548

Shepardson, 2011, Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies, Arch. Neurol., 68, 1239, 10.1001/archneurol.2011.203

Shepardson, 2011, Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations, Arch. Neurol., 68, 1385, 10.1001/archneurol.2011.242

Simons, 1998, Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons, Proc. Natl. Acad. Sci. USA, 95, 6460, 10.1073/pnas.95.11.6460

Smith, 1964, A newly recognized syndrome of multiple congenital anomalies, J. Pediatr., 64, 210, 10.1016/S0022-3476(64)80264-X

Sparks, 1994, Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol, Exp. Neurol., 126, 88, 10.1006/exnr.1994.1044

Strittmatter, 1993, Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease, Proc. Natl. Acad. Sci. USA, 90, 8098, 10.1073/pnas.90.17.8098

Tan, 2012, B-site APP-cleaving enzyme 1 trafficking and Alzheimer’s disease pathogenesis, J. Neurochem., 120, 869, 10.1111/j.1471-4159.2011.07623.x

Ujiie, 2003, Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model, Microcirculation, 10, 463

Umeda, 2012, Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer’s disease model mice, Life Sci, 10.1016/j.lfs.2011.12.022

Valenza, 2005, Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease, J. Neurosci., 25, 9932, 10.1523/JNEUROSCI.3355-05.2005

Valenza, 2010, Cholesterol defect is marked across multiple rodent models of Huntington’s disease and is manifest in astrocytes, J. Neurosci., 30, 10844, 10.1523/JNEUROSCI.0917-10.2010

Vance, 2010, Transfer of cholesterol by the NPC team, Cell Metab., 12, 105, 10.1016/j.cmet.2010.07.004

Vance, 2010, Formation and function of apolipoprotein E-containing lipoproteins in the nervous system, Biochim. Biophys. Acta, 1801, 806, 10.1016/j.bbalip.2010.02.007

Vanier, 2003, Niemann-Pick disease type C, Clin. Genet., 64, 269, 10.1034/j.1399-0004.2003.00147.x

Vaughan, 2004, Update on statins: 2003, Circulation, 110, 886, 10.1161/01.CIR.0000139312.10076.BA

Veinbergs, 1998, Altered long-term potentiation in the hippocampus of apolipoprotein E-deficient mice, Neurosci. Lett., 249, 71, 10.1016/S0304-3940(98)00399-1

Wahrle, 2004, ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE, J. Biol. Chem., 279, 40987, 10.1074/jbc.M407963200

Wahrle, 2005, Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease, J. Biol. Chem., 280, 43236, 10.1074/jbc.M508780200

Wahrle, 2008, Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease, J. Clin. Invest., 118, 671

Wang, 2010, Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes, Cell Metab., 12, 166, 10.1016/j.cmet.2010.05.016

Wolozin, 2000, Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors, Arch. Neurol., 57, 1439, 10.1001/archneur.57.10.1439

Xue, 2011, Crystal structure of amyloid precursor-like protein 1 and heparin complex suggests a dual role of heparin in E2 dimerization, Proc. Natl. Acad. Sci. USA, 108, 16229, 10.1073/pnas.1103407108

Yu, 2011, Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration, Hum. Mol. Genet., 20, 4440, 10.1093/hmg/ddr372